TGF-beta is a multifunctional immunomodulator with immunosuppressive as well as proinflammatory actions. TGF-beta coordinates events critical to the progression and resolution of inflammatory responses. This complex coordination involves recruitment of inflammatory cells, activation of lymphocytes, modulation of macrophage function, and expression of adhesion molecules by endothelial cells, monocytes, and lymphocytes. Of the three isoforms found in mammals, TGF-beta1 is the predominant isoform that affects these immune functions in vivo. Therefore, it was not unexpected that the targeted disruption of the TGF-beta1 gene in our mice resulted in a lethal phenotype characterized by progressive multifocal inflammation. We had previously identified some of the molecular mechanisms underlying this complex immune dysregulation. We further demonstrated that more than half of the null mice die in utero, and that this embryonic lethality is associated with defects in early hematopoiesis and vasculature in the embryonic yolk sac. Live-born TGF-beta1 null mice exhibit onset of inflammation as early as postnatal day 7, coincident with enhanced expression of both classes of MHC molecules and increased adhesion of leukocytes to the vascular endothelium. In subsequent analyses, we found that the null mice also exhibit autoimmune manifestations such as elevated levels of antibodies to nuclear antigens and kidney deposits of immune complexes. We have also demonstrated that this autoimmune phenotype can be transferred by bone marrow transplantation of bone marrow cells from the null mice to lethally-irradiated wild-type mice. Interestingly, our studies with the synthetic peptides corresponding to cell- and heparin-binding sequences of fibronectin indicate their ameliorating effects on the null mouse, especially in reducing the adhesion of lymphocytes to the vascular endothelium and reducing inflammation in the salivary and lachrymal glands. Enhanced expression of MHC class -I and- II antigens in TGF-beta1 null mice suggested that both of these antigens have important roles in the development of the autoimmune reactions in these mice. We subsequently characterized the role of MHC class II antigens by generating TGF-beta1/MHC-II double null mice. These mice are without any evidence of inflammatory infiltrates, circulating autoantibodies or glomerular immune complex deposits. Instead, these mice exhibit extramedullary hematopoiesis and survive slightly longer than the TGF-beta1 null mice. Thus, MHC class II antigens are essential for the expression of autoimmunity in the TGF-beta1 null mice and may normally cooperate with this growth factor to regulate hematopoiesis. To delineate the precise role of MHC class I molecules in the pathogenesis of TGF-beta1 null mice, we generated TGF-beta1 null mice in the genetic background of MHC class I/?2-microglobulin (?2M) deficiency. ?2M null mice lack expression of MHC class I antigen and peripheral CD8+ T cells because ?2M is essential for the proper assembly, transport and cell surface expression of the MHC class I heterodimers of heavy and light chains. Kaplan-Meier analysis showed a significant improvement in survival of the TGF-beta1/beta2M double null mice. While the tissue distribution of inflammatory lesions was similar to that found in TGF-beta1 null mice, the severity of inflammation was significantly reduced in the double null mice, especially in the heart. Flow cytometric analysis revealed reduced levels of CD8+ T cells in the thymus, spleen and lymph node, suggesting impaired T cell development in thymus. These mice also exhibited increased myelopoiesis with decreased inflammation. Moreover, these mice had significantly reduced levels of circulating autoantibodies and glomerular immune complex deposits. These results thus indicate that MHC class I molecules influence the development of the autoimmunity and inflammation seen in TGF-beta1 null mice, and CD8+ T cells may contribute to the inflammation in these mice. To assess the therapeutic potential of circulating levels of active TGF-b1, we generated mice with endocrine expression of active TGF-b1 on a TGF-b1 null background (TGF-b1(-/-/TG)) by crossing TGF-?1(+/-) mice with transgenic mice (TG) that express TGF-?1 in liver and secrete in the blood. The TGF-b1(-/-/TG) mice exhibit a survival profile similar to the TGF-b1 (-/-) mice indicating a failure to rescue lethal phenotype. However, serum TGF-?1 levels in theTGF-b1 (-/-/TG) mice were restored to normal level, with expression in all the tissues notably in the kidney and spleen. Histopathology showed reduced inflammation in all target tissues, especially in the heart. Interestingly unlike TGF-b (-/-) mice, the TGF-b1(-/-/TG) mice have glomerulonephritis in their kidneys similar to the TG mice. Thus, the phenotype of TGF-b1 (-/-/TG) animal model indicates the potential role of circulating active-TGF-?1 in reducing inflammation but it failure to rescue lethality in TGF-?1 null mice indicates critical role of autocrine TGF-?1. Currently, work is underway to study isform specific role of TGF-beta isoforms and also to target its expression to specific cell types.